Tumor infiltrating lymphocytes (TIL) have been identified that can recognize unique cancer antigens on murine and human cancer in an MHC restricted fashion. In clinical trials of TIL administration, 36% of patients with metastatic melanoma underwent objective cancer remission. TIL trafficked to and accumulated in cancer deposits. Utilizing TIL capable of mediating in vivo regression, six genes encoding tumor antigens have been identified. The MART-1 and gp100 antigens, restricted by HLA- A2, the tyrosinase antigen (HLA-A24) and the TRP-1 antigen (HLA-A31) are normal nonmutated differentiation antigens present in melanomas and normal melanocytes. The TRP-1 antigen, was translated from an open reading frame different from that of the normal protein. The p15 antigen, restricted by HLA-A24, was derived from a normal gene of unknown function which was transcribed in a variety of cells but was only expressed on the cell surface of melanomas. The beta-catenin tumor antigen restricted by HLA- A24, was derived from a normal gene containing a single base mutation that resulted in a single amino acid change. The immunodominant peptides present in these antigens have been identified . There is a single immunodominant peptide in the MART-1 antigen and 5 immunodominant peptides in the gp100 antigen. A series of clinical studies have been initiated utilizing these genes and gene products for the immunotherapy of patients with metastatic melanoma. Patients have been immunized with the immunodominant MART-1 or gp100 peptide in Incomplete Freunds Adjuvant. Studies of peptides containing individual amino acid substitutions designed to increase MHC binding have identified peptides with increased immunogenicity and clinical trials evaluating these are in progress as well. Recombinant vaccinia, adenovirus and fowlpox viruses have been constructed encoding either the MART-1 or gp100 gene and clinical trials evaluating these viruses have recently been initiated in the Surgery Branch, NCI. In vitro immunologic studies have demonstrated that immunization with immunodominant peptides in IFA leads to increased precursor frequencies of reactive lymphocytes. Clinical protocols of the adoptive transfer of peripheral blood lymphocytes sensitized in vitro to the immunodominant peptides have begun.